A Mutation in the DNA Polymerase Accessory Factor of Herpes Simplex Virus 1 Restores Viral DNA Replication in the Presence of Raltegravir

Zhou, Bin; Yang, Kui; Wills, Elizabeth; Tang, Liang; Baines, Joel D.

doi:10.1128/jvi.01540-14

Cited by 18 publications

(29 citation statements)

References 41 publications

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“…42 Compared to HIV-1 viremic women, more women in the HIV-1 aviremic group were currently using raltegravir, although the difference was not statistically significant. There was no correlation between CMV IgG and raltegravir use among HIV-1-positive women currently on cART (data not shown).…”

Section: Clinical Characteristics Of the Study Cohortmentioning

confidence: 95%

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

Lurain

Hanson

Hotton

et al. 2016

AIDS Research and Human Retroviruses

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Three groups of cytomegalovirus (CMV)-seropositive women (total n = 164) were selected from the Chicago Women's Interagency HIV-1 Study to investigate the association between CMV coinfection and immune activation: (1) HIV-1 viremic, (2) HIV-1 aviremic, and (3) HIV-1 uninfected. Quantitative measures of CMV serum IgG, CMV DNA, and serum biomarkers interleukin (IL)-6, soluble CD163 (sCD163), soluble CD14 (sCD14), and interferon gamma-induced protein (IP10) were obtained. Levels of CMV IgG and the serum biomarkers were significantly higher in the HIV-1 viremic group compared to the aviremic and uninfected groups ( p < 0.001). No significant associations with CMV IgG levels were found for HIV-uninfected women. When each of the HIVinfected groups was analyzed, sCD14 levels in the viremic women were significantly associated with CMV IgG levels with p < 0.02 when adjusted for age, CD4 count, and HIV viral load. There was also a modest association ( p = 0.036) with IL-6 from plasma and cervical vaginal lavage specimens both unadjusted and adjusted for CD4 count and HIV viral load. The association of CMV IgG level with sCD14 implicates the monocyte as a potential site for interaction of the two viruses, which eventually may lead to non-AIDS-defining pathological conditions.

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Section: Clinical Characteristics Of the Study Cohortmentioning

confidence: 95%

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

Lurain

Hanson

Hotton

et al. 2016

AIDS Research and Human Retroviruses

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“…Potential cytotoxic effects of drugs on PK-15 cells were evaluated by assessing cell viability using the CellTiter 96 AQueous One Solution cell proliferation assay (Promega) as described previously (36). Briefly, subconfluent cell cultures grown in 96-well plates were incubated with various concentrations of drugs for 2 h. After incubation for 24 h at 37°C, 20 l of the manufacturer's reagent was added to the cells.…”

Section: Methodsmentioning

confidence: 99%

Entry of Classical Swine Fever Virus into PK-15 Cells via a pH-, Dynamin-, and Cholesterol-Dependent, Clathrin-Mediated Endocytic Pathway That Requires Rab5 and Rab7

Shi

Liu

Zhou

et al. 2016

J Virol

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Classical swine fever virus (CSFV), a member of the genus Pestivirus within the family Flaviviridae, is a small, enveloped, positive-strand RNA virus. Due to its economic importance to the pig industry, the biology and pathogenesis of CSFV have been investigated extensively. However, the mechanisms of CSFV entry into cells are not well characterized. In this study, we used systematic approaches to dissect CSFV cell entry. We first observed that CSFV infection was inhibited by chloroquine and NH 4 Cl, suggesting that viral entry required a low-pH environment. By using the specific inhibitor dynasore, or by expressing the dominant negative (DN) K44A mutant, we verified that dynamin is required for CSFV entry. CSFV particles were observed to colocalize with clathrin at 5 min postinternalization, and CSFV infection was significantly reduced by chlorpromazine treatment, overexpression of a dominant negative form of the EPS15 protein, or knockdown of the clathrin heavy chain by RNA interference. These results suggested that CSFV entry depends on clathrin. Additionally, we found that endocytosis of CSFV was dependent on membrane cholesterol, while neither the overexpression of a dominant negative caveolin mutant nor the knockdown of caveolin had an effect. These results further suggested that CSFV entry required cholesterol and not caveolae. Importantly, the effect of DN mutants of three Rab proteins that regulate endosomal traffic on CSFV infection was examined. Expression of DN Rab5 and Rab7 mutants, but not the DN Rab11 mutant, significantly inhibited CSFV replication. These results were confirmed by silencing of Rab5 and Rab7. Confocal microscopy showed that virus particles colocalized with Rab5 or Rab7 during the early phase of infection within 45 min after virus entry. These results indicated that after internalization, CSFV moved to early and late endosomes before releasing its RNA. Taken together, our findings demonstrate for the first time that CSFV enters cells through the endocytic pathway, providing new insights into the life cycle of pestiviruses. IMPORTANCEBovine viral diarrhea virus (BVDV), a single-stranded, positive-sense pestivirus within the family Flaviviridae, is internalized by clathrin-dependent receptor-mediated endocytosis. However, the detailed mechanism of cell entry is unknown for other pestiviruses, such as classical swine fever (CSF) virus (CSFV). CSFV is the etiological agent of CSF, a highly contagious disease of swine that causes numerous deaths in pigs and enormous economic losses in China. Understanding the entry pathway of CSFV will not only advance our knowledge of CSFV infection and pathogenesis but also provide novel drug targets for antiviral intervention. Based on this objective, we used systematic approaches to dissect the pathway of entry of CSFV into PK-15 cells. This is the first report to show that the entry of CSFV into PK-15 cells requires a low-pH environment and involves dynamin-and cholesteroldependent, clathrin-mediated endocytosis that requires Rab5 and Rab7....

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“…The antiviral drug raltegravir, is an FDA-approved retroviral integrase inhibitor which was recently shown to inhibit replication of the human alphaherpesvirus herpes simplex virus type 1 (HSV-1) (Summa et al, 2008;Zhou et al, 2014). Similar to the anti-herpes nucleoside analogues, raltegravir was also capable of inhibiting FHV-1 replication in the feline corneal explant system.…”

Section: Discussionmentioning

confidence: 99%

“…The retroviral integrase inhibitor raltegravir inhibits FHV-1 replication in both CRFK cells and the whole corneal explant model Based on the recent reports that retroviral integrase inhibitors are also effective against herpesviruses (Yan et al, 2014;Zhou et al, 2014), we decided to explore the potential of this class of antiviral drugs against FHV-1 in the whole corneal explant model. The retroviral integrase inhibitor raltegravir was used as it is currently approved for use in humans for the treatment of human immunodeficiency virus infection (Summa et al, 2008), and was recently shown to be safe for use in cats (Boesch et al, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, it was also recently found that raltegravir, a currently available retroviral integrase inhibitor approved by the US Food and Drug Administration (FDA) in 2007 (Summa et al, 2008), was able to interfere with UL42, the DNA polymerase accessory factor of the human alphaherpesvirus HSV-1 (Zhou et al, 2014). Based on the fact that (i) the FHV-1-encoded UL42 shares 24 % amino acid sequence similarity with HSV-1 UL42 (Zhukovskaya et al, 2014) and (ii) raltegravir appears safe to administer systemically to cats (Boesch et al, 2015), raltegravir could be an attractive novel antiviral drug to treat ocular herpesvirus infection in cats.…”

Section: Introductionmentioning

confidence: 99%

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A novel corneal explant model system to evaluate antiviral drugs against feline herpesvirus type 1 (FHV-1)

Pennington

Fort

Ledbetter

et al. 2016

Journal of General Virology

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Feline herpesvirus type-1 (FHV-1) is the most common viral cause of ocular surface disease in cats. Many antiviral drugs are used to treat FHV-1, but require frequent topical application and most lack well-controlled in vivo studies to justify their clinical use. Therefore, better validation of current and novel treatment options are urgently needed. Here, we report on the development of a feline whole corneal explant model that supports FHV-1 replication and thus can be used as a novel model system to evaluate the efficacy of antiviral drugs. The anti-herpes nucleoside analogues cidofovir and acyclovir, which are used clinically to treat ocular herpesvirus infection in cats and have previously been evaluated in traditional two-dimensional feline cell cultures in vitro, were evaluated in this explant model. Both drugs suppressed FHV-1 replication when given every 12 h, with cidofovir showing greater efficacy. In addition, the potential efficacy of the retroviral integrase inhibitor raltegravir against FHV-1 was evaluated in cell culture as well as in the explant model. Raltegravir was not toxic to feline cells or corneas, and most significantly, inhibited FHV-1 replication at 500 µM in both systems. Importantly, this drug was effective when given only once every 24 h. Taken together, our data indicate that the feline whole corneal explant model is a useful tool for the evaluation of antiviral drugs and, furthermore, that raltegravir appears a promising novel antiviral drug to treat ocular herpesvirus infection in cats.

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A Mutation in the DNA Polymerase Accessory Factor of Herpes Simplex Virus 1 Restores Viral DNA Replication in the Presence of Raltegravir

Cited by 18 publications

References 41 publications

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

Entry of Classical Swine Fever Virus into PK-15 Cells via a pH-, Dynamin-, and Cholesterol-Dependent, Clathrin-Mediated Endocytic Pathway That Requires Rab5 and Rab7

A novel corneal explant model system to evaluate antiviral drugs against feline herpesvirus type 1 (FHV-1)

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